Macrocyclic compounds pounds and methods of use thereof

ABSTRACT

The invention features novel macrocyclic compounds, methods of making the compounds, pharmaceutical compositions including the compounds, and methods of treatment using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/241,514, filed Sep. 30, 2005, now U.S. Pat. No. 7,767,797, whichclaims the benefit of priority to U.S. provisional patent applicationSer. No. 60/614,260, filed Sep. 30, 2004; Ser. No. 60/615,876, filedOct. 6, 2004; and Ser. No. 60/635,512, filed Dec. 14, 2004 nowabandoned. The contents of each of these applications are incorporatedherein by reference in their entirety.

BACKGROUND

Macrocyclic lactones, and in particular, the “azalides” aresemi-synthetic compounds with a range of biological activities. Amongstthe best known of these is antibiotic activity through binding to thebacterial ribosome. The compounds do, however, have a range of otheractivities including anti-inflammatory activity (see, e.g., EP0283055).In recent years, it has been proposed that macrocycles may have broaderapplication as drug carriers in which an active substance is reversiblybonded to the macrocycle via an ester bond (see, e.g., PCT 03/070174).

Various observations have linked the anti-bacterial activity ofmacrolides to the interaction between the hydroxyl group on thedesosamine ring and the bacterial ribosome. Modification of thisposition on the macrolide, should, therefore, reduce anti-bioticactivity while providing for alternative interactions with other targetproteins.

A large number of researchers have reported derivatives with variationin this part of the molecule including Kobrehel et al. Also reported aresubstitutions on the macrolactone ring or modification of the sugarresidues (for example, cladinose to carbonyl in the case of theketolides). However, the majority of this work has been performed withthe objective of designing new molecules having antibiotic activity.

SUMMARY OF THE INVENTION

This invention relates to novel, semisynthetic macrocycles related toerythromycin or the azalide series or compounds, particularly toderivatives of erythromycin and azithromycin, and to pharmaceuticallyacceptable addition salts thereof, to a process and intermediates forthe preparation thereof, and to their use in the preparation ofpharmaceuticals for the treatment of inflammations, neoplasms,cardiovascular diseases metabolic diseases and infections amongst otherdisease areas.

In one aspect, the invention provides a compound represented by thestructure:

wherein:

-   R¹=OH, O-acyl, N₃, NH₂NH₂, NR₂, in which R is independently for each    occurrence H, alkyl, aryl, or heteroaryl;-   R²=OH, O-acyl, NR₂, in which R is independently for each occurrence    H, alkyl, aryl, or heteroaryl;-   R³=H, OH, O-alkyl, O-acyl

R⁴=H

R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O

R⁶═H, methyl,

R⁷, R⁸═H, acyl, or R⁷, R⁸=CO (cyclic carbonate); or a pharmaceuticallyacceptable salt thereof;

with the proviso that the compound is not azithromycin.

In another aspect, the invention provides a compound represented by theformula:

wherein

A and A′ are each hydrogen or taken together form a double bond, and A″is H or OH or O-Cladinosyl;

or A=Hydrogen and A′ and A″ taken together represent ═O;

R¹, R², R³, and R⁵ are independently selected from the group consistingof H, alkyl, acyl, allyl, vinyl, SiR′₃ in which R′ is, independently foreach occurrence, alkyl or aryl);

R², R³ may be C═O (cyclic carbonate);

-   R⁶═H, OH, CN, N₃, NR⁸ ₂ (in which each R⁸ is independently H, alkyl    or cycloalkyl), alkyl, cycloalkyl, —N(CH₃)R^(8′) (in which R^(8′) is    H, alkyl, aryl, heteroaryl), or SR⁹ (in which R⁹ is H, alkyl or    cycloalkyl);

Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or —CH₂—N(Y)—,

wherein Y═H, alkyl, aryl, heteroalkyl, heteroaryl, allyl,alkylheteroaryl, O-Alkyl or O-aryl;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound represented by thestructure (Formula I):

in which Macrolide is a macrocylic macrolide moiety selected from thegroup consisting of macrolides, macrolactones and azalides.

In another aspect, the invention provides a method of making a compoundof Formula I, the method comprising heating a 3-N′,N′-dialkyl-amino N′oxide desosamine macrolide compound under conditions such that a3′,4′-olefinic macrolide (more preferably an azalide) is formed.

In another aspect, the invention provides a compound represented by thestructure (Formula II):

in which Macrolide is a macrolide moiety selected from the groupconsisting of macrolides, macrolactones and azalides. In preferredembodiments, the compound is represented by the structure:

In another aspect, the invention provides a method of making a compoundof Formula II, the method including the step of treating a3′,4′-olefinic desosamino compound with an epoxidizing reagent underconditions such that the compound of Formula II is prepared.

In another aspect, the invention provides a method for purifying a2′,3′-epoxy macrolide. The method includes the steps of a) providing the2′,3′-epoxy macrolide; b) contacting the 2′,3′-epoxy macrolide with anaqueous solvent and a base under conditions such that the 2′,3′-epoxymacrolide precipitates; and c) collecting the precipitated 2′,3′-epoxymacrolide. In preferred embodiments, the macrolide is an azalide. Inpreferred embodiments, the method includes the further step ofrecrystallizing the precipitated 2′,3′-epoxy macrolide.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of claim Formula III herein, or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptableexcipient.

In Formula III, R¹=OH, O-acyl, N₃, NH₂NH₂, NR₂ (in which both R residuescan independently mean: H, alkyl, aryl, or heteroaryl);

-   R²=OH, O-acyl, NR₂ (in which both R residues can independently mean:    H, alkyl, aryl, or heteroaryl);-   or R¹ and R² may independently represent more complex residues, for    example mono- or oligofunctional moieties (polyamines, bicyclic    systems, peptides amines, halogenides, sulphonic esters, acetals,    esters, aldehydes, sulfones, sulfonamides, lactones, boronates,    silicates, hydroxylamines, alcohols or any type of heterocycle such    as imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);-   R³=H, OH, O-alkyl, O-acyl

R⁴=H

R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O

R⁶=H, methyl,

R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate);

with the proviso that the compound is not azithromycin;

or a pharmaceutically acceptable salt thereof.

In still another aspect, the invention provides a pharmaceuticalcomposition comprising a compound of claim Formula X herein, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable excipient.

In Formula X, A and A′ are Hydrogen or taken together form a double bondand A″ is H or OH or O-Cladinosyl;

or A=Hydrogen and A′ and A″ taken together represent ═O;

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate);

-   R⁶═H, OH, CN, N₃, NR⁸ ₂ (R⁸ in this context may be, e.g., H or alkyl    or cycloalkyl), alkyl, cycloalkyl, —N(CH₃)R⁸ (R⁸ in this context may    be, e.g., H, alkyl, aryl, or heteroaryl; however, it will be    understood by the skilled artisan that more complex residues may be    represented by this position, for example mono- or oligofunctional    moieties or even pharmacophores or otherwise a desired activity    causing assembly of chemical building blocks), or SR⁹ (R⁹ in this    context may be H or alkyl or cycloalkyl);-   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or —CH₂—N(Y)—    where Y═H, alkyl, aryl, heteroalkyl, heteroaryl, allyl or    alkylheteroaryl or O-Alkyl or O-aryl;    or a pharmaceutically acceptable salt thereof.

In yet another aspect, the invention provides a method of treating aninflammatory, viral, bacterial, cardio-vascular modulators, metabolic orimmune disorder. The method includes administering to a subject in needthereof an effective amount of a compound of Formula III herein, suchthat the inflammatory, viral, bacterial, cardio-vascular modulators,metabolic or immune disorder is treated.

In yet another aspect, the invention provides a method of treating aninflammatory, viral, bacterial, cardio-vascular modulators, metabolic orimmune disorder. The method includes administering to a subject in needthereof an effective amount of a compound of Formula X herein, such thatthe inflammatory, viral, bacterial, cardio-vascular modulators,metabolic or immune disorder is treated.

Other advantages, objects, and features of the invention will beapparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the structure of certain compounds of the invention(Compound A and Compound B).

FIG. 2. is a graph showing the response of murine blood cells to varyingconcentrations of a compound of the invention (see Example 31) based onthe production of the chemotactic cytokine “KC”. Fresh mouse whole bloodwas stimulated by LPS and incubated for 90 minutes. KC was quantified bybioplex.

DETAILED DESCRIPTION

This invention relates to novel, semisynthetic macrocycles related tothe erythromycine and azalide series, particularly to derivatives oferythromycin and azithromycin and to pharmaceutically acceptableaddition salts thereof, to a process and intermediates for thepreparation thereof, and to their use in the preparation ofpharmaceuticals for the treatment of inflammations, neoplasms, metabolicdiseases, cardiovascular diseases and infections.

According to the invention, it is possible to exploit a wide range ofmacrocycle structures for diverse pharmaceutical uses with reduceddanger of promoting bacterial resistance to this drug class amongst thepatient population.

It is well known that macrocyclic compounds present good physical andpharmaceutical properties, however, their antibacterial action restrictsbroader uses. However, due to their complex structure, furtherderivatization can be difficult, especially on large scale. To allowboth reduction in antibacterial activity and facile, high yieldingderivative formation, it would be desirable to find methods forpreparation of reactive intermediates and facile purification methods.

Thus, according to the present invention, macrocycles may beconveniently modified at the secondary hydroxyl and amine on thedesosamine ring.

The modifications can have at least three main effects:

-   -   Changes in physical properties    -   Reduction in antibiotic activity in some examples    -   Addition of sites for derivatisation to add functional groups        including pharmacophores and heterocycles.

Exemplary modifications include but are not limited to: grouptranspositions, eliminations, reductive amination, mesylation,halogenation, tosylation, oxidation, alkylation, formation of epoxides,Amino derivatives, intra-lactone ring cyclisations, substitutions ofhydroxyl groups for amine groups, removal of amines, addition ofreactive sites (e.g. bromo, hydroxyl etc.), exchanges of sugars forcyclic or aliphatic groups, combinations of these modifications. Theproducts and/or intermediates derived from these modifications can befurther modified chemically via hydrolysis (including removal ofcladinose), oxidation (includes formation of ketones), reductiveamination, acylation, alkylation, nucleophilic substitution,rearrangements among others. On the intermediates prepared from theseprocesses, pharmacophore or functionalized moieties can be attached.Without wishing to be bound by any particular theory, it is believedthat the modifications change ring geometry, modifying activity andphysical properties such as polarity, which in turn may alter permeationand formulation properties in addition to changes in the activity of thesubstance as an anti-biotic, anti-inflammatory, anti-proliferative andother activities. The resulting substances may also be conjugated withother active substances (such as drugs) so as to act as a prodrug. Theinvention also features a means of treating disease and formulations ofthese substances in pharmacologically acceptable vehicles.

The compounds so derived from macrocyclic starting points may serve asanti-inflammatory compounds, protease inhibitors, anti-viral compounds,anti-bacterial compounds, modulators of ion-channels, inhibitors ofneurodegeneration, cardio-vascular modulators, metabolic modulators andimmune modulators.

The invention allows the design of macrocycles that can be selectivelymodified to promote their activity as drug carriers and scaffolds forfurther derivatisation toward structures with direct drug-like activitywithout at the same time maintaining complete or partial (even lessdesirable) anti-biotic activity.

In the present invention this concept is elaborated using epoxideproducts from the erythromycin-derived macrocycles and the azalide classof macrocycles.

The invention features:

-   -   Formation of two types of epoxides on the desosamine ring of a        macrolide and purifying the product by an up-scalable process.    -   Further reaction of the epoxides with nucleophiles.    -   Substitution with low molecular weight groups with reactive        sites.    -   Further derivatisation of the reactive groups with complex        substituents.    -   These changes provide highly functionalized molecules that can        be utilized according to user-specification (i.e. structurally        diverse libraries of compounds, building blocks, pharmacophores,        drug scaffolds, drug carriers, etc.)    -   3′-N-demethylamino derivatives of azithromycin, erythromycin or        related macrolides, containing an oxiranyl, oxiranylalkyl or        oxiranylaryl, or halogen-alkyl, halogenaryl, sulfonic ester,        aminoaryl, aminoalkyl substituent to the 3′-amino function    -   Further reaction of these activated intermediates with small        molecules containing one or several groups such as aldehyde,        amino, hydrazino, azido, carboxy, hydroxy, boronates, cyano, and        malono or malonate functions or bifunctional 1,3-carbonyl or        carboxyl reagents.    -   Further derivatisation of these activated intermediates with        complex molecules especially leading to ring formation or        further bond formation, in particular, aromatic, heteroaromatic,        heterocyclic ring systems with substitutions including bromo,        fluoro, chloro, hydroxy, cyano, carbonyl, carboxamide,        sulphonamide, amino, amido, mercapto, sulfonyl, sulfanyl.    -   Usage of functionalised intermediates to synthesise        macrolide-substituted derivatives of known functional molecules        including, but not limited to sterols, nuclear receptor ligands,        kinase inhibitors, nucleosides, anti-inflammatory structures or        protease inhibitors.

DEFINITIONS

Before further description of the present invention, and in order thatthe invention may be more readily understood, certain terms are firstdefined and collected here for convenience.

A “therapeutic agent,” as used herein, is a molecule withpharmacological activity (e.g., a therapeutic agent, medicine,medicament, or active agent), a disease modification agent, or any othermolecule or fragment of a therapeutic agent that can be covalentlyattached to a macrocycle via a bond or a linker which may have adesirable mode of action in target cells.

The term “cyclic” refers to a hydrocarbon cyclic ring including fullysaturated, partially saturated, and unsaturated mono-, bi, andtri-cyclic rings having 4 to 34 ring atoms, preferably, 7 to 10, or 10to 15 ring atoms. The term “heterocyclic” refers to a hydrocarbon cyclicring including fully saturated, partially saturated, and unsaturatedmono-, bi, and tri-cyclic rings having 4 to 34 ring atoms, preferably, 7to 10, or 10 to 15 ring atoms having one or more heteroatoms, such as S,O, or N in each ring.

The term “sugar” refers to a mono-, di-, or tri-saccharide includingdeoxy-, thio-, and amino-saccharides. Examples of sugars include, butare not limited to, furanose and pyranose.

The terms “halogen” and “halo” refer to radicals of fluorine, chlorine,bromine or iodine.

The terms “macrolactone” or “macrocycle” are known in the art and referto compounds having large lactone ring (i.e., cyclic ester) having atleast 10 ring atoms. The term “macrolide” refers to a chemical compoundcharacterized by a large lactone ring (having at least 10 ring atoms)containing one or more keto and hydroxyl groups, or to any of a largegroup of antibacterial antibiotics containing a large lactone ringlinked glycosidically to one or more sugars; they are produced bycertain species of Streptomyces and inhibit protein synthesis by bindingto the 50S subunits of 70S ribosomes. Examples include erythromycin,azithromycin, and clarithromycin. The term “ketolide” refers to achemical compound characterized by a large lactone ring (having at least10 ring atoms) containing one or more keto groups.

The term “alkyl” (or “alkenyl” or “alkynyl”) refers to a hydrocarbonchain that may be a straight chain or branched chain, containing theindicated number of carbon atoms. For example, C₁-C₁₀ indicates that thegroup may have from 1 to 10 (inclusive) carbon atoms in it. Alkenylgroups and alkynyl groups have one or more double or triplecarboN-carbon bonds, respectively, in the chain.

The term “aryl” refers to a hydrocarbon ring system (monocyclic orbicyclic) having the indicated number of carbon atoms and at least onearomatic ring. Examples of aryl moieties include, but are not limitedto, phenyl, naphthyl, and pyrenyl.

The term “heteroaryl” refers to a ring system (monocyclic or bicyclic)having the indicated number of ring atoms including carbon atoms and atleast one aromatic ring. The ring system includes at least oneheteroatom such as O, N, or S (e.g., between 1 and 4 heteroatoms,inclusive, per ring) as part of the ring system. Examples of heteroarylmoieties include, but are not limited to, pyridyl, furyl or furanyl,imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl,quinolinyl, indolyl, and thiazolyl.

The term “alkoxy” refers to an —O-alkyl radical.

The term “cycloalkyl” refers to a nonaromatic hydrocarbon ring system(monocyclic or bicyclic), containing the indicated number of carbonatoms.

The term “heterocycloalkyl” refers to a nonaromatic ring system(monocyclic or bicyclic), containing the indicated number of ring atomsincluding carbon atoms and at least one heteroatom such as O, N, or S(e.g., between 1 and 4 heteroatoms, inclusive, per ring) as part of thering system.

The term “effective amount” includes an amount effective, at dosages andfor periods of time necessary, to achieve the desired result, e.g.,sufficient to treat a cell proliferative disorder. An effective amountof compound of the invention may vary according to factors such as thedisease state, age, and weight of the subject, and the ability of thecompound of the invention to elicit a desired response in the subject.Dosage regimens may be adjusted to provide the optimum therapeuticresponse. An effective amount is also one in which any toxic ordetrimental effects (e.g., side effects) of the compound of theinvention are outweighed by the therapeutically beneficial effects.

The term “subject” includes organisms which are capable of sufferingfrom a disease or disorder, e.g., as described herein (including aninflammatory, viral, bacterial, cardio-vascular modulators, metabolic orimmune disorder), or who could otherwise benefit from the administrationof a compound of the invention, such as human and non-human animals.Preferred humans include human patients suffering from or prone tosuffering from a disease or disorder or associated state, as describedherein (including an inflammatory, viral, bacterial, cardio-vascularmodulators, metabolic or immune disorder). The term “non-human animals”of the invention includes all vertebrates, e.g., mammals, e.g., rodents,e.g., mice, and non-mammals, such as non-human primates, e.g., sheep,dog, cow, chickens, amphibians, reptiles, etc.

The compounds described herein have a range of utilities including useas anti-inflammatory compounds, protease inhibitors, inhibitors ofneuro-degeneration, anti-viral compounds, anti-bacterial compounds,modulators of ion-channels, cardio-vascular modulators, metabolicmodulators and immune modulators. In many instances, their utility maybe related to effects on cells of the macrophage type either asphagocytes or antigen presenting cells. Such an example is seen incardiovascular diseases such as atherosclerosis where there is a stronginflammatory component to the events that result in the thickening andfragmentation of the vessel obstructing plaques. This inflammation maybe effectively reduced by the application of a range of agents thatinteract with the macrophage class.

The compounds described herein include the compounds themselves, as wellas their salts, including pharmaceutically acceptable salts, ifapplicable. Such salts, for example, can be formed between a positivelycharged substituent (e.g., amino) on a compound and an anion. Suitableanions include, but are not limited to, chloride, bromide, iodide,sulfate, nitrate, phosphate, citrate, methanesulfonate,trifluoroacetate, and acetate. Likewise, a negatively chargedsubstituent (e.g., carboxylate) on a compound can form a salt with acation. Suitable cations include, but are not limited to, sodium ion,potassium ion, magnesium ion, calcium ion, and an ammonium cation suchas tetramethylammonium ion.

In addition, some of the compounds of this invention have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms.

Further, the aforementioned compounds also include their N-oxides. Theterm “N-oxides” refers to one or more nitrogen atoms, when present in acompound, are in N-oxide form, i.e., N→O.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., treating a disease).

Process for Preparing and/or Purifying 2′,3′-Epoxides of Macrocycles

As described herein, macrocycles may be conveniently modified at theamino function on the desosamine ring (position 3′). It has now beenfound that a good starting point for performing transformation chemistryon macrolide antibiotics and their derivatives is generating an epoxideon the desosamine ring. One example of an epoxidation reaction isdescribed in PCT03/070174 (Burnet et al) and PCT03/070173 (Burnet et al)where a laboratory scale process is reported. Although adequate fordiscovery purposes, this process was not optimal for large scalechemistry. The process described herein provides for superior yields andpurity in larger scale.

In PCT03/070174 (Burnet et al) and PCT03/070173 (Burnet et al) it hasbeen already disclosed that treating a solution of azithromycin in DMFwith an excess of epichlorohydrin at temperatures between 60 and 120° C.yields a less polar product. This product was identified to be anepoxide (the 2′,3′ desosamine epoxide, see, e.g., Example 1). Withoutwishing to be bound by theory, the reaction mechanism may involve thealkylation of the dimethyl amino group followed by displacement with the2′-hydroxyl group. In these earlier references, purification of theproduct was then usually carried out by chromatography on silica gel.

The present inventors have now discovered a straightforward, up-scalableprocess for performing the elimination/epoxide-formation reaction andpurifying of the reaction product.

Thus, in one aspect, the present invention provides a method forpurifying a 2′,3′-epoxy macrolide (preferably an azalide). The methodincludes the steps of: a) providing the 2′,3′-epoxy macrolide; b)contacting the 2′,3′-epoxy macrolide with an aqueous solvent and a baseunder conditions such that the 2′,3′-epoxy macrolide precipitates; andc) collecting the precipitated 2′,3′-epoxy macrolide. In preferredembodiments, the macrolide is an azalide, even more preferably aderivative of azithromycin. In preferred embodiments, the step ofproviding the macrolide comprises preparing the macrolide, e.g., byreacting a macrolide with an alkylating reagent such as epichlorohydrin,such that the 2′,3′-epoxy macrolide is prepared. The reaction may occurin a solvent, such as DMF. The step of contacting can include adding the2′,3′-epoxy macrolide (preferably after removing at least some of thesolvent from the reacting step) to a solvent mixture which includes atleast some water (e.g., 20%, 40%, 60% or 80% water) preferably mixedwith a water-miscible organic solvent.

The process involves carrying out the epoxidation/elimination reactionand then removing most of the excess reagents (such as epichlorohydrin)and the DMF by transferring the viscous residue into a stirred vesselcontaining water with a certain content of a water miscible solvent(e.g., isopropanol, acetone, methyl or ethyl alcohol) and a base (e.g.,an inorganic base like alkali hydroxides (such as sodium, potassium, orlithium hydroxides) or carbonates (such as sodium, potassium, or lithiumcarbonates). Frequently, precipitation of the epoxide product will takeplace that can be assisted with seeding and/or ultrasonication.Collection of the product by filtration after some period to allowfurther precipitation will yield a crude product that can be easilypurified, e.g., by crystallisation, e.g., from hot isopropanol.Concentration of the mother liquor may yield a second crop of solid thatcan be similarly purified by recrystallisation from isopropanol. Yieldsare typically between 30 and 55%. Advantageously, no chromatographicpurification is necessary.

In certain preferred embodiments: epichlohydrin is used to causeelimination of the 3-dimethylamino moiety of the macrolide and epoxideformation; the epoxide product is isolated from the reaction mixtureusing a water miscible organic solvent; the water miscible organicsolvent is an alcohol; the water miscible organic solvent is used at atemperature of 0 to 15 C; the crude 2′,3′-epoxide product isrecrystallised from an organic solvent, more preferably isopropanol.

Production of Olefinic Compounds by Cope Elimination

The present inventors have discovered that it is also possible togenerate a previously-unknown different epoxide (the 3′,4′-epoxide) onthe desosamine sugar of azalides. Thus, the present invention providesnovel epoxide-containing compounds and methods for their preparation anduse.

In general, the methods of synthesis of the new compounds featuresgeneration of a tertiary amine oxide on the 3-dimethylamino moiety ofthe aminosugar portion of the macrolide. This can be achieved bytreating an azalide macrolide, for example azithromycin with anoxidising agent (e.g., hydrogen peroxide or a peracid like aceticperacid or 3-chloroperbenzoic acid (MCBPA)). Heating of such an amineoxide can lead to formation of an olefinic double bond by elimination ofa hydroxylamine. This reaction is known as the Cope Elimination andtypically occurs with heating of the amine oxide compound, e.g., tobetween 80 and 160° C.

In general, the reaction requires heating to a temperature of 130-230°C., preferably a temperature between 150-170° C. The compound can beheated, e.g., under vacuum in a glass oven (Kugelrohr apparatus). Thereaction can be performed in an inert reaction medium like a highboiling hydrocarbon like xylene, mesytylene or paraffin oil, but morepreferably is performed neat (without solvent) while applying a vacuumof 0.1-30 mbar. Under these conditions a product such as the olefinderived from azithromycin may be formed as a honey-like liquid at hightemperature and a glass like solid upon cooling. Purification can beachieved simply by taking up the reaction product in an organic solventlike ethyl acetate or acetonitrile and filtration of the solutionthrough a pad of silica gel and elution with the same solvent.Evaporation of the solvent can yield a solid that is pure enough formost reactions and can be further purified by recrystallisation, e.g.,from acetonitrile.

The product obtained by this procedure is a versatile starting point formany transformations, including but not limited to epoxidation,bishydroxylation, aminohydroxylation, reduction, oxidation, palladiumcatalyzed acrylic or vinylic coupling and others. Products obtained byany of these transformations may be further derivatised by reactiontyped cited above or other ones, for example nucleophilic reaction of anamine or an organometallic nucleophile on an epoxide. One of manypossible transformations is the epoxidation of the product obtained fromthe Cope elimination step. Opening the epoxide with dimethylamine underappropriate conditions will result after reduction of generally formedtertiary amine oxide during the epoxidation reaction in the formation ofthe sugar mycaminose instead of desosamine in the parent compound ofazithromycin.

The invention thus provides certain 3′,4′-olefinic macrolide compounds.In one aspect, the invention provides a compound which is a3′,4′-olefinic macrolide. In one embodiment, the invention provides acompound represented by the formula (Formula I):

in which Macrolide is a macrocylic macrolide moiety selected from thegroup consisting of macrolides, macrolactones and azalides. In apreferred embodiment, the macrolide is the macrocyclic ring ofazithromycin (together with the associated cladinose sugar). Theinvention also provides pharmaceutically acceptable salts of compoundsof Formula I.

In another aspect, the invention provides a method of making a3′,4′-olefinic macrolide, e.g., a compound of Formula I, the methodcomprising heating a 3-N′,N′-dialkyl-amino N′ oxide (preferablyN,N-dimethylamino) macrolide compound under conditions such that a3′,4′-olefinic azalide is formed. In a preferred embodiment, themacrolide is the macrocyclic ring of azithromycin (together with theassociated cladinose sugar). The method optionally includes the step ofisolating or purifying the compound of Formula I.

Production of 3′,4′-Epoxy Macrolide Compounds by Cope Elimination

The 3′,4′ double bond of a 3′,4′-olefinic macrolide compound of theinvention (e.g., a compound of Formula I, e.g., a compound produced bythe methods described herein), can be subjected to conditions that willresult in epoxide formation on the desosamine. A typical reagent toachieve this transformation is an oxidizing reagent such as3-chloroperbenzoic acid (MCBPA). Under these conditions, any remainingtertiary amine of the macrolide (e.g., N−1 of the macrolide) may alsoreact and be converted to an amine oxide. See, e.g., Compound B of FIG.1 for an example of such a chemical structure.

In one aspect, the invention provides a 3′,4′-epoxy macrolide compound,e.g., a compound represented by the formula (Formula II):

in which Macrolide is a macrolide moiety selected from the groupconsisting of macrolides, macrolactones and azalides. In a preferredembodiment, the macrolide is the macrocyclic ring of azithromycin(together with the associated cladinose sugar). The invention alsoprovides pharmaceutically acceptable salts of compounds of Formula II.

In a preferred embodiment, the 3′,4′-epoxy macrolide compound isrepresented by the structure:

In another aspect, the invention provides a method of making a3′,4′-epoxy macrolide compound of Formula II. The method includes thesteps of: a) treating a compound of Formula II with an epoxidizingreagent under conditions such that the compound of Formula II isprepared. The method optionally includes the step of isolating orpurifying the compound of Formula II.

Elaboration of Epoxides to Yield Pharmacologically-Active Molecules

Chemical structures such as the epoxymacrolides of the invention (e.g.,Compound A of FIG. 1) are well suited for chemical derivatisation due tothe reactive epoxide moiety. Combining Compound A with differentnucleophiles can generate a multitude of compounds. Because themacrocycle backbone provides for good solubility and membranepermeability, these products do not generally suffer from the typicaldisadvantages typically encountered while constructing simple chemicallibraries like poor physico-chemical properties and low watersolubility. Indeed, the large macrocycle can confer superior properties,such as oral availability, cellular penetration, intracellularaccumulation, and the like.

Elaboration of the epoxide-containing compounds of the invention (e.g.,2′,3′-epoxides such as Compound A and 3,4-epoxides such as Compound B ofFIG. 1) can be carried out with inorganic or organic salts like alkaliazides, cyanides, acetates, thiocyanates, neutral nucleophiles likealiphatic, aromatic, heteroaromatic amines or heterocycles containing anamine like imidazole. Substituted or unsubstituted hydrazines can beused. Also salts like hydrochlorides of such nucleophiles can beemployed, e.g. hydroxylamine hydrochloride. Another class of compoundsis represented by carbon nucleophiles including esters of malonic acid.It has to be noted that a nucleophilic molecule or moiety can attack theepoxide principally on two sites, generally yielding a mixture ofproducts, thus increasing the scope of the reaction and the variabilityof the products. It has also to be noted that a moiety entering theepoxide-macrolide at the 2′-position will give rise to a compound with adifferent regiochemistry than for example azithromycin. A dramaticdecrease of antibacterial activity is possible in such a case.

Advantageously, derivatization may take place through either a mono oran oligofunctional molecule so that further chemistry in one or severalfollowing steps may take place. For example, substitution with ammoniawill generate a primary amine which can be subjected to alkylation(e.g., reductive alkylation with aldehydes, or nucleophilic alkylationwith, e.g., an alkyl halide, see, e.g., the Examples herein). Reactionof the epoxide moiety with a diamine like piperazine offers anotherreaction site for subsequent alkylation or acylation reactions.Alkylations may for example be performed with dibromopropane. In thiscase, an additional electrophilic site ready for further displacement isprovided; for example, a bromide may react with hydrazine which in turnwill react to form pyrazole derivatives on exposure to1,3-dicarbonyl/carboxyl derivatives.

Complex structures can be built on macrolides such as Compounds A or B(FIG. 1). These structures may include pharmacophores for a variety ofmolecular targets within or outside of a cell. In one aspect, themacrocyclic backbones provide a means for the functionalized moleculesto enter the cells; in another aspect, the macrocycle stabilizes themolecule or makes it easier to prepare, formulate or manufacture.

Another aspect of the invention is that further variation is possibleespecially when the entering group has a basic nature thus making thesugar moiety more resistant towards acidic hydrolysis. For example,acidic hydrolysis will then result in removal of the cladinose sugar. Itis well established that such a modification will greatly diminish theantibiotic potential of a macrolide of this class.

Exemplary compounds, e.g., compounds that can be prepared using theepoxy or olefinic macrolide compounds of the invention, are describedinfra.

Derivatives of N-des-methyl Desosamine Containing Macrocycles

It is known that erythromycin can be easily demethylated at the aminofunction in the 3′-position on the desosamino sugar. This reaction canalso be applied to other macrolide derivatives like azithromycin or2-ethyl-3,4,10-trihydroxy-11-[3-hydroxy-6-methyl-4-(methyl-oxiranylmethyl-amino)-tetrahydro-pyran-2-yloxy]-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-aza-cyclopentadecane-13,15-dione.During examination of the formation of3′-dedimethylamino-2′-dehydroxy-2′,3′-epoxyazithromycin it wassurprisingly found, that the desamination does not occur on thedemethylated derivative of azithromycin, but smoothly leads to theintroduction of an oxiranylmethyl side chain to the nitrogen. Thisreaction can be applied to other 3′-N-demethylmacrolides, too. Otheralkylating agents are also insufficient for desamination, but lead onlyto monoalkylation of the nitrogen in position 3′. In certainembodiments, the reaction is carried out in concentrated solution in2-propanol with an excess of epichlorohydrin in the presence ofpotassium carbonate at room temperature. It usually gives excellentyields; purification can be achieved by recrystallisation.

Exemplary compounds, e.g., compounds that can be prepared fromN-desmethyl desosamine-containing macrocycles, are described infra.

Elaboration of Activated Forms of N-Desmethyl Macrolides

The present invention also relates to the synthesis of differentactivated intermediates that are suitable for further easyderivatisation steps on the desosamine side chain of azithromycin, andthe use of these compounds for the above mentioned purpose. Thisincludes the opening of the epoxide rings with any type of nucleophiles,for example, but not limited to amines, carboxylates, phenols, sulfides,inorganic nucleophiles like hydroxylamines, hydrazines, cyanides, azidesor thiocyanates or C-nucleophiles like malonates or acetoacetates, orsubstitution of alkylhalogenides or other alkylating functions withthese nucleophiles. In certain embodiments, this chemistry is similar tothe chemistries used for elaboration of 2′,3′-epoxy compounds such asCompound A, e.g., as described supra.

The compounds thus formed may be pharmacologically active themselves ormay be starting points for the synthesis of more complex structures;accordingly, the invention includes compounds which incorporatestructural elements of known activity, like, for example, kinaseinhibiting cores or kinase inhibitors or protease inhibitors, linked tothe macrolide core for improvement of their properties, as well asmethods of preparing and using such compounds. Improvement in propertiesis intended to include (but is not limited to) improvements in theirphysical properties, their toxicity, taste, specific activating orinhibiting activity, distribution pattern in an organism or improvedretention or excretion from a body, in comparison to the underivatizedactive compounds.

Compounds

Thus, in one aspect, the invention provides novel compounds. In oneembodiment, the invention provides compounds represented by the formula(Formula III):

wherein:

-   R¹=OH, O-acyl, N₃, NH₂NH₂, NR₂ (in which both R residues can    independently mean: H, alkyl, aryl, heteroaryl);-   R²=OH, O-acyl, NR₂ (in which both R residues can independently mean:    H, alkyl, aryl, heteroaryl);-   or R¹ and R² may independently represent more complex residues, for    example mono- or oligofunctional moieties (polyamines, bicyclic    systems, peptides amines, halogenides, sulphonic esters, acetals,    esters, aldehydes, sulfones, sulfonamides, lactones, boronates,    silicates, hydroxylamines, alcohols or any type of heterocycle such    as imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);-   R³=H, OH, O-alkyl, O-acyl

R⁴=H

R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O

R⁶=H, methyl,

R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate);

with the proviso that the compound is not azithromycin; or apharmaceutically acceptable salt thereof.

In one embodiment, the invention provides compounds represented by theformula (Formula IV):

in which

-   R¹, R²=independently H, alkyl (e.g., C₁-C₁₀ alkyl), aryl, or    heteroaryl; or R¹ and R² may independently represent more complex    residues, for example mono- or oligofunctional moieties (polyamines,    bicyclic systems, peptides amines, halogenides, sulphonic esters,    acetals, esters, aldehydes, sulfones, sulfonamides, lactones,    boronates, silicates, hydroxylamines, alcohols or any type of    heterocycle such as imidazoles, thiazoles pyrimidines and    combinations thereof), pharmacophores (e.g. sterols, hormones,    peptide analogs, nucleosides, anti-inflammatory structures, protease    inhibitors, kinase inhibitors) or specifically reactive functions    (hydrazines, amino groups, 1,3-dicarbonyl or carboxyl groups,    bromoalkyl and bromoaryl groups) that may be conveniently reacted    with reagents to form heterocyclic residues or cyclic or    heterocyclic assemblies);

R³=OH, O-acyl

R⁴=H

R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O

R⁶=H, methyl,

R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate); or a pharmaceuticallyacceptable salt thereof.

In certain preferred embodiments, the invention provides compoundsrepresented by the formula (Formula V):

wherein:

-   R¹, R²=independently H, alkyl (e.g., C₁-C₁₀ alkyl), aryl, or    heteroaryl; or R¹ and R² may independently represent more complex    residues, for example mono- or oligofunctional moieties (polyamines,    bicyclic systems, peptides amines, halogenides, sulphonic esters,    acetals, esters, aldehydes, sulfones, sulfonamides, lactones,    boronates, silicates, hydroxylamines, alcohols or any type of    heterocycle such as imidazoles, thiazoles pyrimidines and    combinations thereof), pharmacophores (e.g. sterols, hormones,    peptide analogs, nucleosides, anti-inflammatory structures, protease    inhibitors, kinase inhibitors) or specifically reactive functions    (hydrazines, amino groups, 1,3-dicarbonyl or carboxyl groups,    bromoalkyl and bromoaryl groups) that may be conveniently reacted    with reagents to form heterocyclic residues or cyclic or    heterocyclic assemblies);

R³=H, acyl, alkyl

R⁴=H

R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O

R⁶=H, methyl,

R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate); or a pharmaceuticallyacceptable salt thereof.

In certain preferred embodiment, the invention provides compoundsrepresented by the formula (Formula VI):

wherein:

-   R¹, R²=independently H, alkyl (e.g., C₁-C₁₀ alkyl), aryl, or    heteroaryl; or R¹ and R² may independently represent more complex    residues, for example mono- or oligofunctional moieties (polyamines,    bicyclic systems, peptides amines, halogenides, sulphonic esters,    acetals, esters, aldehydes, sulfones, sulfonamides, lactones,    boronates, silicates, hydroxylamines, alcohols or any type of    heterocycle such as imidazoles, thiazoles pyrimidines and    combinations thereof), pharmacophores (e.g. sterols, hormones,    peptide analogs, nucleosides, anti-inflammatory structures, protease    inhibitors, kinase inhibitors) or specifically reactive functions    (hydrazines, amino groups, 1,3-dicarbonyl or carboxyl groups,    bromoalkyl and bromoaryl groups) that may be conveniently reacted    with reagents to form heterocyclic residues or cyclic or    heterocyclic assemblies); or R₁ and R₂, taken together with the    nitrogen atom to which they are attached, form a carbocyclic or    heterocyclic ring having one to ten atoms in the ring;-   R³=H, acyl, alkyl

R⁴=H

R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O

R⁶=H, methyl,

R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate); or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula VII):

wherein:

-   R¹, R²=independently H, alkyl (e.g., C₁-C₁₀ alkyl), aryl, or    heteroaryl; or R¹ and R² may independently represent more complex    residues, for example mono- or oligofunctional moieties (polyamines,    bicyclic systems, peptides amines, halogenides, sulphonic esters,    acetals, esters, aldehydes, sulfones, sulfonamides, lactones,    boronates, silicates, hydroxylamines, alcohols or any type of    heterocycle such as imidazoles, thiazoles pyrimidines and    combinations thereof), pharmacophores (e.g. sterols, hormones,    peptide analogs, nucleosides, anti-inflammatory structures, protease    inhibitors, kinase inhibitors) or specifically reactive functions    (hydrazines, amino groups, 1,3-dicarbonyl or carboxyl groups,    bromoalkyl and bromoaryl groups) that may be conveniently reacted    with reagents to form heterocyclic residues or cyclic or    heterocyclic assemblies); or R₁ and R₂, taken together with the    nitrogen atom to which they are attached, form a carbocyclic or    heterocyclic ring having one to ten atoms in the ring;

R³=H, acyl, alkyl

R⁴=H

R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O

R⁶=H, methyl,

R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate); or a pharmaceuticallyacceptable salt thereof.

However, in preferred embodiments, the compound is not:

In another embodiment, the invention provides compounds represented bythe formula (Formula VIII):

wherein:

-   -   R¹=H, lower alkyl    -   R²=H, OH, O-alkyl, NH₂, NH₂NH₂, halogen, SH, aryl, heteroaryl,        or a combination of several of these elements.    -   R³=H, acyl, alkyl    -   R⁴=H    -   R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O    -   R⁶=H, methyl,    -   R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate); or a        pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula IX):

wherein:

-   -   R¹=H, lower alkyl    -   R²=H, OH, O-alkyl, NH₂, NH₂NH₂, halogen, SH, aryl, heteroaryl,        or a combination of several of these elements.    -   R³=H, acyl, alkyl    -   R⁴=H    -   R⁵=cladinosyl, OH, or R⁴, R⁵ is ═O    -   R⁶=H, methyl,    -   R⁷, R⁸=H, acyl, or R⁷, R⁸=CO (cyclic carbonate); or a        pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula X):

wherein

-   -   A, A′ are Hydrogen or radicals forming a double bond and A″ is H        or OH or O-Cladinosyl;    -   or A=Hydrogen and A′ and A″ are double bound oxygen;        R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl,        SiR₃ (R in this context may be alkyl or a combination of alkyl        and aryl)

R², R³ may be C═O (cyclic carbonate);

-   R⁶=H, OH, CN, N₃, NR⁸ ₂ (R⁸ in this context may be H or alkyl or    cycloalkyl), alkyl, cycloalkyl, —N(CH₃)R⁸ (R⁸ in this context may be    H, alkyl, aryl, heteroaryl; it will be understood by the skilled    artisan that more complex residues may be represented by this    position, for example mono- or oligofunctional moieties or even    pharmacophores or otherwise a desired activity causing assembly of    chemical building blocks), or SR⁹ (R⁹ in this context may be H or    alkyl or cycloalkyl);-   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or —CH₂—N(Y)—    where Y═H, alkyl, aryl, heteroalkyl, heteroaryl, allyl or    alkylheteroaryl or O-Alkyl or O-aryl;    or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XI):

wherein

A ═OH or O-cladinosyl

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁶=independently H, alkyl (e.g., C₁-C₁₀ alkyl), aryl, or heteroaryl;    or R¹ and R² may independently represent more complex residues, for    example mono- or oligofunctional moieties (polyamines, bicyclic    systems, peptides amines, halogenides, sulphonic esters, acetals,    esters, aldehydes, sulfones, sulfonamides, lactones, boronates,    silicates, hydroxylamines, alcohols or any type of heterocycle such    as imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);-   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or —CH₂—N(Y)—    where Y═H, alkyl, aryl, heteroalkyl, heteroaryl, allyl or    alkylheteroaryl or O-Alkyl or O-aryl; or a pharmaceutically    acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XII):

wherein

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁶=independently H, alkyl (e.g., C₁-C₁₀ alkyl), aryl, or heteroaryl;    or R¹ and R² may independently represent more complex residues, for    example mono- or oligofunctional moieties (polyamines, bicyclic    systems, peptides amines, halogenides, sulphonic esters, acetals,    esters, aldehydes, sulfones, sulfonamides, lactones, boronates,    silicates, hydroxylamines, alcohols or any type of heterocycle such    as imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);-   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or —CH₂—N(Y)—    where Y═H, alkyl, aryl, heteroalkyl, heteroaryl, allyl or    alkylheteroaryl or O-Alkyl or O-aryl;    or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XIII)

wherein

A ═OH or O-cladinosyl

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁴ and R^(4′) may be independently H, alkyl, heteroalkyl,    cycloalkyl, heterocycloalkyl, vinyl, allyl, acyl, aryl, heteroaryl,    alkylaryl, alkylheteroaryl; or independently H, alkyl (e.g., C₁-C₁₀    alkyl), aryl, or heteroaryl; or R⁴ and R^(4′) may independently    represent more complex residues, for example mono- or    oligofunctional moieties (polyamines, bicyclic systems, peptides    amines, halogenides, sulphonic esters, acetals, esters, aldehydes,    sulfones, sulfonamides, lactones, boronates, silicates,    hydroxylamines, alcohols or any type of heterocycle such as    imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);    -   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or        —CH₂—N(Y)— where Y═H, alkyl, aryl, heteroalkyl, heteroaryl,        allyl or alkylheteroaryl or O-Alkyl or O-aryl;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XIV):

wherein

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁴ and R^(4′) may be independently H, alkyl, heteroalkyl,    cycloalkyl, heterocycloalkyl, vinyl, allyl, acyl, aryl, heteroaryl,    alkylaryl, alkylheteroaryl; or R⁴ and R^(4′) may independently    represent more complex residues, for example mono- or    oligofunctional moieties (polyamines, bicyclic systems, peptides    amines, halogenides, sulphonic esters, acetals, esters, aldehydes,    sulfones, sulfonamides, lactones, boronates, silicates,    hydroxylamines, alcohols or any type of heterocycle such as    imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);    -   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or        —CH₂—N(Y)— where Y═H, alkyl, aryl, heteroalkyl, heteroaryl,        allyl or alkylheteroaryl or O-Alkyl or D-aryl;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XV):

wherein

A ═OH or O-cladinosyl

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁴ may be H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,    vinyl, allyl, acyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl; or    R⁴ may also represent more complex residues, for example mono- or    oligofunctional moieties (polyamines, bicyclic systems, peptides    amines, halogenides, sulphonic esters, acetals, esters, aldehydes,    sulfones, sulfonamides, lactones, boronates, silicates,    hydroxylamines, alcohols or any type of heterocycle such as    imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);    -   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or        —CH₂—N(Y)— where Y═H, alkyl, aryl, heteroalkyl, heteroaryl,        allyl or alkylheteroaryl or O-Alkyl or D-aryl;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XVI):

wherein

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁴ and R^(4′) may be independently H, alkyl, heteroalkyl,    cycloalkyl, heterocycloalkyl, vinyl, allyl, acyl, aryl, heteroaryl,    alkylaryl, alkylheteroaryl; or R⁴ and R^(4′) may independently be H,    alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, vinyl, allyl,    acyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl; or R⁴ may also    represent more complex residues, for example mono- or    oligofunctional moieties (polyamines, bicyclic systems, peptides    amines, halogenides, sulphonic esters, acetals, esters, aldehydes,    sulfones, sulfonamides, lactones, boronates, silicates,    hydroxylamines, alcohols or any type of heterocycle such as    imidazoles, thiazoles pyrimidines and combinations thereof),    pharmacophores (e.g. sterols, hormones, peptide analogs,    nucleosides, anti-inflammatory structures, protease inhibitors,    kinase inhibitors) or specifically reactive functions (hydrazines,    amino groups, 1,3-dicarbonyl or carboxyl groups, bromoalkyl and    bromoaryl groups) that may be conveniently reacted with reagents to    form heterocyclic residues or cyclic or heterocyclic assemblies);    -   Q=—(C═O)— or —(C═NY)— or —N(CH₃)—CH₂— or —N(Y)—CH₂—, or        —CH₂—N(Y)— where Y═H, alkyl, aryl, heteroalkyl, heteroaryl,        allyl or alkylheteroaryl or O-Alkyl or O-aryl;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XVII):

wherein

A ═OH or O-cladinosyl

X═H or OH or NH(R). R in this context means H, lower alkyl or aryl.

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁴ may be H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,    vinyl, allyl, acyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl; it    will be understood by the skilled artisan that more complex residues    may be represented by this position, for example mono- or    oligofunctional moieties or even pharmacophores or otherwise a    desired activity causing assembly of chemical building blocks);

Q=—(C═O)— or —N(CH₃)—CH₂—;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides compounds represented bythe formula (Formula XVIII):

wherein

X═H or OH or NH(R), in which R is H, lower alkyl or aryl.

R¹-R³, and R⁵ are independently H, alkyl, acyl, allyl, vinyl, SiR₃ (R inthis context may be alkyl or a combination of alkyl and aryl)

R², R³ may be C═O (cyclic carbonate)

-   R⁴ may be may be independently H, alkyl, heteroalkyl, cycloalkyl,    heterocycloalkyl, vinyl, allyl, acyl, aryl, heteroaryl, alkylaryl,    alkylheteroaryl; or R⁴ and R^(4′) may independently be H, alkyl,    heteroalkyl, cycloalkyl, heterocycloalkyl, vinyl, allyl, acyl, aryl,    heteroaryl, alkylaryl, alkylheteroaryl; or R⁴ may also represent    more complex residues, for example mono- or oligofunctional moieties    (polyamines, bicyclic systems, peptides amines, halogenides,    sulphonic esters, acetals, esters, aldehydes, sulfones,    sulfonamides, lactones, boronates, silicates, hydroxylamines,    alcohols or any type of heterocycle such as imidazoles, thiazoles    pyrimidines and combinations thereof), pharmacophores (e.g. sterols,    hormones, peptide analogs, nucleosides, anti-inflammatory    structures, protease inhibitors, kinase inhibitors) or specifically    reactive functions (hydrazines, amino groups, 1,3-dicarbonyl or    carboxyl groups, bromoalkyl and bromoaryl groups) that may be    conveniently reacted with reagents to form heterocyclic residues or    cyclic or heterocyclic assemblies);

Q=—(C═O)— or —N(CH₃)—CH₂—;

or a pharmaceutically acceptable salt thereof.

Methods of Treatment

In another aspect, this invention features a method for treating aninflammatory, viral, bacterial, cardio-vascular modulators, metabolic orimmune disorder. The method includes administering to a subject in needthereof an effective amount of a compound described herein. Optionally,the method includes co-usage with other anti-inflammatory agents ortherapeutic agents. Without wishing to be bound by any particulartheory, it is believed that the use of the compounds described hereinimproves therapy at least in part because of the preferential access ofthe compounds to immune cells including neutrophils, monocytes,eosinophils, macrophage, alveolar macrophage, B and T-lymphocytes, NKcells, giant cells, Kupfer cells, glial cells, and similar target cells.

Compounds prepared according to the methods described above areexemplified herein and examples of their biological activity arerecorded in Table 3. From these data, it can be seen that the variousderivatives are able to modulate the synthesis or release of cytokinesor small molecule signaling substances such as NO. These effects aredose responsive and vary with structure. For example, the modulation ofthe neutrophil migration factor KC by a compound of the invention (seeExample 31) has an EC₅₀ in the order of 100 nM.

In one embodiment, the invention provides a method of treating aninflammatory disorder, the method including administering to a subjectin need thereof an effective amount of a compound of the invention,e.g., a compound of one of Formulas I-XVIII (more preferably Formula IIIor Formula X), such that the inflammatory disorder is treated.

In another embodiment, the invention provides a method of treating aninfectious disease, the method including administering to a subject inneed thereof an effective amount of a compound of the invention, e.g., acompound of one of Formulas I-XVIII (more preferably Formula III orFormula X), such that the infectious disease is treated.

In another embodiment, the invention provides a method of treatingcancer, the method including administering to a subject in need thereofan effective amount of a compound of the invention, e.g., a compound ofone of Formulas I-XVIII (more preferably Formula III or Formula X), suchthat the cancer is treated.

In another embodiment, the invention provides a method of treatingallergy, the method including administering to a subject in need thereofan effective amount of a compound of the invention, e.g., a compound ofone of Formulas I-XVIII (more preferably Formula III or Formula X), suchthat the allergy is treated.

In another embodiment, the invention provides a method of treating animmune disorder, the method including administering to a subject in needthereof an effective amount of a compound of the invention, e.g., acompound of one of Formulas I-XVIII (more preferably Formula III orFormula X), such that the immune disorder is treated.

In another embodiment, the invention provides a method of treating ahematopoietic disorder, the method including administering to a subjectin need thereof an effective amount of a compound of the invention,e.g., a compound of one of Formulas I-XVIII (more preferably Formula IIIor Formula X), such that the hematopoietic disorder is treated.

In another embodiment, the invention provides a method of treating ametabolic disease, the method including administering to a subject inneed thereof an effective amount of a compound of the invention, e.g., acompound of one of Formulas I-XVIII (more preferably Formula III orFormula X), such that the metabolic disease is treated.

In another embodiment, the invention provides a method of treating ametabolic disease, the method including administering to a subject inneed thereof an effective amount of a compound of the invention, e.g., acompound of one of Formulas I-XVIII (more preferably Formula III orFormula X), such that the metabolic disease is treated.

Determination of a therapeutically effective amount or aprophylactically effective amount of the compound of the invention ofthe invention, can be readily made by the physician or veterinarian (the“attending clinician”), as one skilled in the art, by the use of knowntechniques and by observing results obtained under analogouscircumstances. The dosages may be varied depending upon the requirementsof the patient in the judgment of the attending clinician; the severityof the condition being treated and the particular compound beingemployed. In determining the therapeutically effective amount or dose,and the prophylactically effective amount or dose, a number of factorsare considered by the attending clinician, including, but not limitedto: the specific disease or disorder involved; pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the desired time course of treatment; the species ofsubject; its size, age, and general health; the specific diseaseinvolved; the degree of or involvement or the severity of the disease;the response of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the kind of concurrent treatment (i.e., the interaction of thecompound of the invention with other co-administered therapeutics); andother relevant circumstances.

Treatment can be initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage may be increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired.

Pharmaceutical Compositions

The present invention also features a pharmaceutical compositionincluding at least one compound of this invention and a pharmaceuticallyacceptable carrier. Optionally, the pharmaceutical composition includesone or more other therapeutic agents.

This invention further features a method for making any of the compoundsdescribed above. The method includes taking any intermediate compounddelineated herein, reacting it with any one or more reagents to form acompound of this invention including any processes specificallydelineated herein.

Also within the scope of this invention are a pharmaceutical compositionincluding one or more of the compounds of this invention, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable excipient. The pharmaceutical compositions,optionally including one or more other therapeutic agents, can be usedin treating various diseases, e.g., as described above. The inventionalso features the use of a compound or composition of the invention forthe manufacture of a medicament for the treatment of disease.

To practice the method of treating a disease or disorder, the compoundsof this invention can be administered to a patient, for example, inorder to treat a disease described above. The compound can, for example,be administered in a pharmaceutically acceptable carrier such asphysiological saline, in combination with other therapeutic agents,and/or together with appropriate excipients. The compound describedherein can, for example, be administered by injection, intravenously,intraarterially, subdermally, intraperitoneally, intramuscularly, orsubcutaneously; or orally, buccally, nasally, transmucosally, topically,in an ophthalmic preparation, by inhalation, by intracranial injectionor infusion techniques, with a dosage ranging from about 0.1 to about 20mg/kg of body weight, preferably dosages between 10 mg and 1000 mg/dose,every 4 to 120 hours, or according to the requirements of the particulartherapeutic agent. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Lower or higher doses than those recited abovemay be required. Specific dosage and treatment regimens for anyparticular patient will depend upon a variety of factors, including theactivity of the specific compound employed, the age, body weight,general health status, sex, diet, time of administration, rate ofexcretion, therapeutic agent combination, the severity and course of thedisease, condition or symptoms, the patient's disposition to thedisease, condition or symptoms, and the judgment of the treatingphysician.

Pharmaceutical compositions of this invention comprise a compound ofthis invention or a pharmaceutically acceptable salt thereof; and anypharmaceutically acceptable carrier, adjuvant or vehicle. Suchcompositions may optionally comprise additional therapeutic agents. Thecompositions delineated herein include the compounds of the formulaedelineated herein, as well as additional therapeutic agents if present,in amounts effective for achieving a modulation of a disease.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying therapeutic agent delivery systems (SEDDS)such as D-alpha-tocopherol polyethyleneglycol 1000 succinate,surfactants used in pharmaceutical dosage forms such as Tweens or othersimilar polymeric delivery matrices, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as I-, θ-, and K-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-θ-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein. Oil solutions or suspensionsmay also contain a long-chain alcohol diluent or dispersant, orcarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage forms suchas emulsions and or suspensions.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carriersthat are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions of this invention may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

A suitable in vitro assay can be used to preliminarily evaluate acompound of this invention in treating a disease. In vivo screening canalso be performed by following procedures well known in the art.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

The invention will be further described in the following examples. Itshould be understood that these examples are for illustrative purposesonly and are not to be construed as limiting this invention in anymanner.

EXAMPLES Example 1 2′-deoxy-3′-dedimethylamino-2′,3′-epoxyazithomycin

A suspension of 26 g of azithromycin in 17 ml of DMF was heated to 70°C. and 7.5 ml of epichlorohydrin is added. The mixture is stirred at thesame temperature for 8 h. After this period another 4 ml ofepichlorohydrine is added and heating and stiffing continued for 12 h.After this period most of the volatiles are removed in vacuum at 60° C.The residue is treated with 100 ml of isopropanol and 50 ml of water andthe slurry is transferred into a vessel containing 200 ml of water and 4g of potassium carbonate. Precipitation occurs and the mixture isstirred at ambient temperature for 12 h to complete precipitation. Thesolid (about 14 g) was filtered off to yield the crude product. Thatproduct was redissolved in 80 ml of hot isopropanol and filtered. Thefiltrate was allowed to cool, yielding 9.5 g of the pure product.

Example 2 3′-dedimethylamino-4′-dehydroazithromycin

12 g of azithromycin 3′-N-oxide was heated in a Kugelrohr apparatus to150-155° C. while applying a vacuum of 20 mbar. After 1 h at thistemperature the flask was cooled and the clear brownish oil taken up inethyl acetate. The solution was filtered through a pad of silica gel (20cm×3 cm), elution with ethyl acetate. Evaporation of the solvent yieldeda slightly brown solid that can be used without further purification orcan be subjected to recrystalisation from hot acetonitrile. C¹³-NMR:178.4, 132.2, 126.3, 102.1, 94.8, 83.3, 77.9, 74.1, 73.5, 7.8, 69.9,68.6, 65.3, 60.2, 49.3, 45.2, 42.2, 41.8, 36.2, 34, 6, 27.2, 26.5, 21.9,21.4, 21.1, 20.8, 17.8, 16.1, 14.7, 14.1, 11.1, 9.1, 7.2.

Example 33′-dedimethylamino-4′-dehydro-3′,4′-epoxyazithromycin-1-N-oxide

A solution of 3 g of the product obtained as described in example 2 in12 ml of dichloromethane was treated with 4 g of mCPBA (75%) in severalportions within 1 h. After 7 h the mixture was diluted with 70 ml ofdichloromethane. The solution was washed with sodium sulfite solution,sodium carbonate solution and brine. Evaporation yielded a white solidthat was used without purification.

Example 4 4′-hydroxyazithromycin

700 mg of the product obtained as described above was heated in 2 ml ofdimethylamine at 75° C. for 48 h. After cooling the contained was openedand the excess dimethylamine removed in vacuum. The residue was taken upin 3 ml of methanol and heated to reflux in the presence of 300 mg ofammonium formate and 50 mg of Palladium on charcoal (10%). The methanolwas evaporated and the residue was taken up in dichloromethane andfiltered through silica gel, elution with ethyl acetate containing 2% oftriethylamine to yield the product, Rf=0.3[dichloromethane:isopropanol:ammonia (7 M in methanol) 20:1:1].

Example 5

A solution of 3.0 g of azithromycin in 15 ml of dry DMF is heatedtogether with 4 g of sodium azide to reflux for 10 h. After cooling themixture was poured into 5% aqueous citric acid (200 ml) and thenextracted with ethyl acetate (3×100 ml). The aqueous phase was treatedwith potassium carbonate until basic and then extracted with ethylacetate. The organic phase was washed with brine, dried with (sodiumsulfate) and concentrated under vacuum. The residue was chromatographedon silica gel, elution with chloroform:isopropanol:ammonia (solution inMeOH) 30:1:1 (Rf=0.09) to yield an off white solid. MS: 573 (M+1).

Example 63′-[1,4]-diazepan-1-yl-3′-desdimethylaminoazithromycin/2′-[1,4]-diazepan-1-yl-2′-dehydroxy-3′-desdimethylamino-3′-hydroxyazithromycin

A solution of 150 mg of2′-deoxy-3′-dedimethylamino-2′,3′-epoxyazithomycin, prepared as inexample 1, and 60 mg of homopiperazine in 3 ml of DMF is heated to 70°C. for 12 h. After cooling the mixture is partitioned between ethylacetate and water. The ethyl acetate phase was washed several times withwater and brine, dried over sodium sulfate and concentrated in vacuum toyield the crude mixture of regioisomeres in roughly the same amounts.The crude product was used without further purification.

Example 7 N-3′-(3-bromopropyl)-N-3′-desmethylazithromycin

A mixture of 3.0 g of 3′-demethylazithromycin, 4 g of potassiumcarbonate and 5 ml of 1,3-dibromopropane was stirred in 20 ml of DMF at50° C. for 24 h. After cooling all volatiles were removed in vacuum andthe residue partitioned between water and ethyl acetate. The organicphase was washed with brine, dried over sodium sulfate and concentratedto yield a residue that was used without further purification.

Example 8 N-3′-(4-bromobutyl)-N-3′-desmethylazithromycin

The compound was prepared in the same way as forN-3′-(3-bromopropyl)-N-3′-demethylazithromycin (example 7) bysubstituting 1,3-dibromopropane by 1,4-dibromobutane.

Example 9 N-3′-(6-bromohexyl)-N-3′-desmethylazithromycin

The compound was prepared in the same way as forN-3′-(3-bromopropyl)-N-3′-demethylazithromycin (example 7) bysubstituting 1,3-dibromopropane by 1,6-dibromohexane.

Example 10N-3′-(3-bromopropyl)-N-3′-desmethyl-3-decladinosylazithromycin

The title compound was prepared in the same way asN-3′-(3-bromopropyl)-N-3′-demethylazithromycin (example 7) bysubstituting 3′-desmethylazithromycin with3′-desmethyl-3-decladinosylazithromycin.

Example 11 N-3′-(6-bromohexyl)-N-3′-desmethyl-3-decladinosylazithromycin

The compound was prepared in the same way asN-3′-(3-bromopropyl)-N-3′-desmethylazithromycin (example 7) bysubstituting 3′-demethylazithromycin with3′-N-desmethyl-3-decladinosylazithromycin and 1,3-dibromopropane with1,6-dibromohexane.

Example 12 N-3′-(6-aminohexyl)-N-3′-desmethyl-3-decladinosylazithromycin

120 mg of N-3′-(6-bromohexyl)-N-3′-desmethyl-3-decladinosylazithromycin(example 11) was added to 12 ml of a solution of ammonia in methanol (7M). After stiffing for 48 h all volatiles were evaporated in vacuum andthe residue partitioned between aqueous potassium carbonate and ethylacetate. The organic phase was washed with brine, dried over sodiumsulfate and concentrated to yield a residue that was used withoutfurther purification.

Example 13 N-3′-(4-aminobutyl)-N-3′-desmethylazithromycin

The compound was prepared in the same way asN-3′-(6-aminohexyl)-N-3′-desmethyl-3-decladinosylazithromycin (example12) by substitutingN-3′-(6-bromohexyl)-N-3′-desmethyl-3-decladinosylazithromycin byN-3′-(4-bromobutyl)-N-3′-desmethylazithromycin.

Example 14 N-3′-(3-hydrazinopropyl)-N-3′-desmethylazithromycin

To a solution of 4 ml of hydrazin hydrate in 15 ml of DMF was added 800mg of N-3′-(3-bromopropyl)-N-3′-desmethylazithromycin (example 7). Afterstirring for 24 h at 40° C. all volatiles were removed in vacuum and theresidue partitioned between aqueous potassium carbonate and ethylacetate. The organic phase was washed with brine, dried over sodiumsulfate and concentrated to yield a residue that was used withoutfurther purification.

Example 15 N-3′-glycidyl-N-3′-desmethylazithromycin

A suspension of 3 g of 3′-demethylazithromycin in 15 ml of isopropanolwas stirred with 2 ml of epichlorohydrin for 24 h. All volatiles wereremoved then and the residue partitioned between water, potassiumcarbonate and ethyl acetate. The organic phase was washed with brine,dried over sodium sulfate and concentrated to yield a residue that wasused without further purification.

Example 16N-3′-glycidyl-N-3′-desmethyl-3-decladinosyl-3-dehydro-3-oxoazithromycin

The compound was prepared in the same way as forN-3′-glycidyl-N-3′-desmethylazithromycin (example 15) by substitutingN-3′-glycidyl-N-3′-desmethylazithromycin forN-3′-desmethyl-3-decladinosyl-3-dehydro-3-oxoazithromycin.

Example 17N-3′-{3-[(m-glycidyloxy)-phenoxy]-2-hydroxypropyl}-3′-N-desmethylazithromycin

A solution of 120 mg of 3′-N-desmethylazithromycin and 100 mg ofresorcinol bisglycidylether in 3 ml of DMSO is heated to 100° C. for 4h. After cooling the mixture is partitioned between ethyl acetate andwater. The ethyl acetate phases are washed several times with brine,dried over sodium sulfate and concentrated in vacuum to yield a crudeproduct that was used without further purification.

Example 18 3′-N-(3-azido-2-hydroxypropyl)-3′-N-desmethylazithromycin

A solution of 45 mg of N-3′-glycidyl-N-3′-desmethylazithromycin (example15) in 1 ml of DMSO was treated with 30 mg of sodium azide at 70° C. for8 h. After cooling the mixture was partitioned between ethyl acetate andwater. The ethyl acetate phase was washed with brine, dried over sodiumsulfate and concentrated to yield the desired product.

Example 19 N-3′-p-aminobenzyl-N-3′-desmethylazithromycin

A solution of 700 mg of N-3′-desmethylazithromycin in 5 ml of DMF istreated with 210 mg of nitrobenzylbromide and 200 mg of potassiumcarbonate. After 6 h the mixture was poured onto water and extractedwith ethyl acetate. The organic extract was washed with brine, driedover sodium sulfate and concentrated in vacuum. The residue was usedwithout further purification. The material was dissolved in 20 ml ofmethanol and stirred under an atmosphere of hydrogen in the presence of200 mg of 3% palladium on charcoal for 2 d. The mixture was thenfiltered, the filtrate concentrated and the residue chromatographed onsilica gel, elution with chloroform/isopropanol/ammonia (7 M inmethanol) 60:1:1 to yield the desired product.

Example 20 N-3′-p-bromobenzyl-N-3′-desmethylazithromycin

A solution of 700 mg of N-3′-desmethylazithromycin in 5 ml of DMF istreated with 250 mg of p-bromobenzylbromide and 200 mg of potassiumcarbonate. After 6 h the mixture was poured onto water and extractedwith ethyl acetate. The organic extract was washed with brine, driedover sodium sulfate and concentrated in vacuum. The residue was usedwithout further purification

Example 21N-3′-[3-(p-formylphenyloxy)-2-hydroxypropyl]-N-3′-desmethylazithromycin

A solution of 100 mg of N-3′-glycidyl-N-3′-desmethylazithromycin(example 15) in 3 ml of DMF was treated with 100 mg of potassiumcarbonate and 25 mg of p-hydroxybenzaldehyde at 50° C. for 24 h. Aftercooling the mixture was partitioned between water and ethyl acetate andthe ethyl acetate phase was washed several times with 20% potassiumcarbonate solution. The organic phase was washed with brine, dried oversodium sulfate and concentrated in vacuum. The residue was used withoutfurther purification.

Example 22 N-3′-(3-amino-2-hydroxypropyl)-N-3′-desmethylazithromycin

To 10 ml of a solution of ammonia in methanol (7 M) was added 1.5 g ofN-3′-desmethylazithromycin. After 24 h all volatiles were evaporated andthe residue partitioned between water, potassium carbonate and ethylacetate. The organic phase was washed with brine, dried over sodiumsulfate and concentrated to yield a residue that was used withoutfurther purification.

Example 23

A mixture of 200 mg of the product obtained as described in example 1together with 90 mg of aminopropyl dibutyl amine in 2 ml of isopropanolwas heated for 24 h at 90° C. After cooling the mixture was poured ontowater and extracted with ethyl acetate. The combined organic extractswere washed (brine,) dried (sodium sulfate) and concentrated in vacuum.The residue was taken up in 1 M hydrochloric acid and kept at ambienttemperature for 2 h. After this period the ph was adjusted to >10 withpotassium carbonate and the mixture was extracted with ethyl acetate.The combined organic extracts were washed (brine), dried (sodiumsulfate) and concentrated in vacuum. The residue was chromatographed onsilica gel, elution with chloroform/isopropanol/ammonia 20:1:1 to yieldthe mixture of the title compounds.

Example 24

A mixture of 200 mg of product obtained as described in example 1 and 2g of triphenyl phosphine was heated in a Kugelrohr apparatus to 230° C.while applying a vacuum of about 25 mmbar. The temperature was kept forabout 45 min, then the flask was cooled and the content taken up in 20ml of ethyl acetate. The mixture was extracted with cold 5% citric acid(4×15 ml) and the combined aqueous extracts were counter washed withethyl acetate (2×10 ml). The pH of the aqueous extracts was adjustedto >10 and the mixture was extracted with ethyl acetate. The combinedorganic extracts were washed (brine) dried (sodium sulfate) andconcentrated in vacuum. The residue was chromatographed on silica gel,elution with chloroform/isopropanol/ammonia 40:1:1 to yield the product.

Example 25

A solution of 130 mg of the3′-N-demethyl-3′-N-(oxiranylmethyl)-azithromycin, prepared as describedabove in example 15, in 1.5 ml of methanol was heated in the presence of0.2 ml of butylamine and 0.5 ml of diisopropylethylamine for 24 h at 85°C. After cooling all volatiles were removed in vacuum and the residueused without further purification, or purified by column chromatographyon silica gel.

This general procedure can be applied to various amines and othernucleophiles, as is exemplified herein below:

Mass Ex. detected num. Nucleophile Product ([M + H]+ 21 ammonia

808 26 spermine

332*

27

836 28

865 29

879 30

965 31

920 32

878 33

920 34

866 35

896 36

921 37

878 38

951 39

933 40

991 41

905 42

899 43

952 44

893 45

852 46

892, 910, 993

47

892 48

891 49

977 50

894 51

896 52

980 53

896 54

862 55

866 56

905 57

866 58 ⁻CN

818 59

901 60

915 61

929 62

943 63

484** 64

483** 65

483** 66

466** * = [M + 3H]³⁺ ** = [M + 2H]²⁺

This procedure may also be applied to other3′-N-demethyl-3′-N-(oxiranylmethyl) macrolide derivatives, i.e.3′-N-demethyl-3′-N-(oxiranylmethyl)-erythromycin (example 67, see below)orN-3′-glycidyl-N-3′-desmethyl-3-decladinosyl-3-dehydro-3-oxoazithromycin(See, e.g., Example 16).

Example 67 3′-N-demethyl-3′-N-(oxiranylmethyl)erythromycin

The compound was synthesised the same way as forN-3′-glycidyl-N-3′-desmethylazithromycin by substituting3′-N-desmethylazithromycin with 3′-N-desmethylerythromycin.

This includes, but is not limited to the following examples:

Mass detected Ex. ([M + H − num. Nucleophile Product H₂O]⁺) 68

858 69

845 70

849 71

917 72

948 73

852 74

903 75

804* 76

386** * = [M + H]⁺, ** = [M + 2H]²⁺

Example 77 N-3′-(4,4-dicyanobutyl)-N-3′-desmethylazithromycin

To a solution of 150 mg malononitrile and 250 mg of potassium t-butoxidein 6 ml of DMSO was added 150 mg ofN-3′-(3-bromopropyl)-N-3′-desmethylazithromycin (example 7). The mixturewas stirred for 12 h and then poured onto ice. The mixture was extractedwith ethyl acetate and the organic extract was washed with brine, driedover sodium sulfate and concentrated in vacuum. The residue waschromatographed on silica gel, elution withchloroform/isopropanol/ammonia (7 M in methanol) 40:1:1 to yield thedesired compound.

Example 78N-3′-(7-,7-dimethoxycarbonylheptyl)-N-3′-demethyl-3-decladinosylazithromycin

To a solution of 150 mg dimethyl malonate and 220 mg of potassiumt-butoxide in 6 ml of DMSO was added 150 mg ofN-3′-(6-bromohexyl)-N-3′-demethyl-3-decladinosylazithromycin (example11). The mixture was stirred for 12 h and then poured onto ice. Themixture was extracted with ethyl acetate and the organic extract waswashed with brine, dried over sodium sulfate and concentrated in vacuum.The residue was chromatographed on silica gel, elution withchloroform/isopropanol/ammonia (7 M in methanol) 40:1:1 to yield thedesired compound.

Example 79N-3′-(5-,5-dimethoxycarbonylpentyl)-N-3′-desmethylazithromycin

The compound was prepared in the same way as forN-3′-(7-,7-dimethoxycarbonylheptyl)-N-3′-demethyl-3-decladinosylazithromycin(example 78) by substitutingN-3′-(6-bromohexyl)-N-3′-demethyl-3-decladinosylazithromycin forN-3′-(4-bromobutyl)-N-3′-desmethylazithromycin.

Example 80

To a mixture of 50 mg of p-hydrazinotoluene hydrochloride and 50 mg ofpotassium carbonate in 2 ml of ethanol was added 120 mg ofN-3′-(5-,5-dimethoxycarbonylpentyl)-N-3′-desmethylazithromycin (example79). The mixture was heated to 70° C. for 8 h. After cooling the mixturewas partitioned between ethyl acetate and 5% potassium carbonatesolution. The combined ethyl acetate extracts were washed with brine,dried over sodium sulfate and concentrated in vacuum. The residue waschromatographed on silica gel; elution withchloroform/isopropanol/ammonia (7 M in methanol) 30:1:1 gave the desiredproduct.

Example 81

120 mg of the mixture of3′[1,4]-diazepaN-1-yl-3′-desdimethylaminoazithromycin/2′-[1,4]-diazepaN-1-yl-2′-dehydroxy-3′-desdimethylamino-3′-hydroxaazithromycin(example 6) was dissolved in 3 ml of DMF. 50 mg of succinic acidmonomethylester and 50 mg of EDCI was added. After 5 h the mixture waspartitioned between water and ethyl acetate and the organic phase waswashed several times with 5% potassium carbonate solution, dried oversodium sulfate and concentrated in vacuum. The residue was taken up in 2ml of methanol. 50 mg of hydroxylamine hydrochloride and 50 ml oftriethylamine was added and the mixture heated to 50° C. for 4 h. Aftercooling all volatiles were removed and the residue partitioned betweenethyl acetate and water. The organic phase was washed with brine, driedover sodium sulfate and concentrate in vacuum to yield the crude mixtureof regioisomeric products.

Example 82

A solution of 70 mg ofN-3′-(3-amino-2-hydroxypropyl)-N-3′-desmethylazithromycin (example 21)and 40 mg of 2-benzyl-3-tert-butoxycarbonylamino-succinic acid 4-methylester in 2 ml of DMF was treated with 100 mg of diisopropylcarbodiimideand 30 mg of hydroxysuccinic imide. After 12 h the mixture was pouredonto water and extracted with ethyl acetate. The organic extract waswashed with brine, dried over sodium sulfate and concentrated in vacuum.The residue was chromatographed on silica gel, elution withchloroform/isopropanol/ammonia (7 M in methanol) 30:1:1 to yield theintermediary methylester that was heated afterwards with a mixture of 2ml of methanol and 2 ml of a 50% solution of hydroxylamine in waterunder argon to 60° C. for 24 h. Removal of all volatiles gave thedesired product.

Example 83

A solution of 120 mg of N-3′-(4-aminobutyl)-N-3′-desmethylazithromycin(example 13), 40 mg of hydroxysuccinic imide and 90 mg of3-benzyl-2-tert-butoxycarbonylamino-N-(2-hydroxy-indaN-1-yl)-succinamicacid in 2 ml of DMF was treated with 70 mg of EDCI at 0° C. The mixturewas stirred at the same temperature for 2 h and then allowed to stir atambient temperature for 12 h. The mixture was partitioned between ethylacetate and aqueous potassium carbonate solution and the organicextracts are washed with brine, dried over sodium sulfate and thenconcentrated in vacuum. The residue was chromatographed on silica gel,elution with chloroform/isopropanol/ammonia (7 M in methanol) 15:1:1 toyield the desired product.

Example 84

To a solution of 90 mg of3-dimethylamino-2-(4-fluoro-phenyl)-1-pyridiN-4-yl-propenone in 5 ml ofethanol was added 210 mg ofN-3′-(3-hydrazinopropyl)-N-3′-desmethylazithromycin (example 14). Themixture was heated to 70° C. for 12 h and then all volatiles wereremoved in vacuum. The residue was chromatographed on silica gel,elution with chloroform/isopropanol/ammonia (7 M in methanol) 40:1:1 toyield the desired compound.

Example 85

To a solution of 90 mg of3-dimethylamino-2-quinoliN-4-yl-1-(3-trifluoromethyl-phenyl)-propenonein 4 ml of ethanol was added 180 mg ofN-3′-(3-hydrazinopropyl)-N-3′-demethyl-3-decladinosylazithromycin(example 14). The mixture was heated to 70° C. for 12 h and then allvolatiles were removed in vacuum. The residue was chromatographed onsilica gel, elution with chloroform/isopropanol/ammonia (7 M inmethanol) 40:1:1 to yield the desired compound.

Example 86

A solution of 80 mg ofN-3′-[3-(p-formylphenyloxy)-2-hydroxypropyl]-N-3′-desmethylazithromycin(example 21) in 2 ml of acetic acid was heated in the presence of 200 mgof ammonium acetate and 50 mg of1-(4-fluoro-phenyl)-2-pyridiN-4-yl-ethane-1,2-dione 1-oxime for 6 h at60° C. After cooling most of the acetic acid was removed in vacuum andthe residue partitioned between ethyl acetate and 15% potassiumcarbonate solution. The combined ethyl acetate extracts were washed withbrine, dried over sodium sulfate and concentrated in vacuum. The residuewas dissolved in methanol and hydrogenated for 48 h under an atmosphereof hydrogen in the presence of 100 mg of 3% palladium on charcoal.Filtration and chromatography of the concentrated filtrate on silicagel, elution with chloroform/isopropanol/ammonia (7 M in methanol)20:1:1 gave the desired product.

Example 87

To a mixture of 100 mg of4-(4-Fluoro-phenyl)-5-pyridiN-4-yl-1,3-dihydro-imidazole-2-thione and100 mg of potassium carbonate in 2 ml of DMSO was added 100 mg ofN-3′-(3-bromopropyl)-N-3′-desmethylazithromycin (example 7). The mixturewas heated to 50° C. for 12 h and after cooling poured onto ice.Extraction with ethyl acetate, washing with brine, drying over sodiumsulfate and concentration yielded a residue that was chromatographed onsilica gel; elution with chloroform/isopropanol/ammonia (7 M inmethanol) 20:1:1 to give the desired product.

Example 88

To a solution of 50 mg of dexamethasone and 20 ul of triethylamine in 2ml of THF was added at 0° C. 25 mg of nitrophenyl chloroformate. After 1h at this temperature 100 mg ofN-3′-(6-aminohexyl)-N-3′-desmethyl-3-decladinosylazithromycin (example12) was added and the mixture allowed standing for 2 h at ambienttemperature. All volatiles were removed in vacuum and the residuepartitioned between ethyl acetate and 5% potassium carbonate solution.The combined ethyl acetate extracts were washed with brine, dried oversodium sulfate and concentrated in vacuum. The residue waschromatographed on silica gel; elution withchloroform/isopropanol/ammonia (7 M in methanol) 40:1:1 gave the desiredproduct.

Example 89

TABLE 3 Activity of various compounds from the above series insuppression of pro- inflammatory responses in isolated cells. Potency inNO IFNg NO suppression (% control) (% control) vs. Macrocycle Side chainat 8 μM at 8 μM Dexamethasone Example desmethyl erythromycin 6.3 37.1Dexamethasone 4.3 3.4 A aminocaprylic acid 0.5 A Spermine 3.5 4.7 26 Aaminoacetaldehyde dimethylacetal 0.5 35 A aminomethylthiazole 0.5 41 Arearrangment of 2-amino-butyrolactone 0.5 46 A butylene diamine 0.6 29descladinosyltetraacetal azithromycin 0.6 no ex A Octylamine 4.4 4.7 31A amylamine 3.7 6.8 32 A 2-ethylhexylamine 3.8 3.2 33 A3-(di-N-butylamino)propylamine 4.3 48.2 49 A 2-propylaminoethanol 4.03.9 50 A 4-methyl-pyridine-2-amine 0.8 42 A Trifluoromethylaniline 5.640.5 43 A piperazine-1-carbaldehyde 0.6 56 A aminoethanol 0.5 no ex B6.0 70.0 67 B 5-methyl-thiazole-2-ylamine 4.3 2.9 68 A2,2-dimethoxyethylamine 0.5 35 A piperidine-4-ol 0.5 47 C TriFaniline17.8 71.3 C Octylamine 3.7 40.5 no ex B triFluoromethylaniline 4.6 3.7 BOctylamine 4.6 11.6 B resorcinol 22.9 85.5 B phenol-heptane 5.3 11.6 72B quinoline-3-carbolic acid 4.9 35.3 B BOC Gly 13.7 89.5 B isoquinolinecarboxylate 29.6 65.5 B fluorobenzoic acid 5.3 37.6 76 B4-hydroxy-benzoic acid methyl ester 19.9 91.3 B 4-methoxy phenol 78.291.6 B phenol 7.2 89.5 B OHquinadine 4.4 3.9 A resorcinol 96.9 99.2 59 Aphenol-heptane 4.4 37.6 no ex A 3-quinoline 7.2 23.4 no ex A boc glycine4.4 3.9 63 A isoquinoline carboxylate 30.9 77.6 65 A 4-fluoro-benzoicacid 5.0 41.6 43 A 4-hydroxy-benzoic acid methyl ester 5.3 63.4 62 Amethoxyphenol 5.7 33.7 60 A Phenol 11.3 75.3 A boronic phenol 15.6 74.261 A OHQuinaldine 4.4 5.5 no ex D quinolin carboxylate 88.8 96.8 75 Dfluorobenzoate 7.4 64.7 76 Desmethyl resorcinol 4.7 4.7 no exazithromycin A = N-3′-glycidyl-N-3′-desmethylazithromycin (see example15) B = 3′-N-demethyl-3′-N-(oxiranylmethyl)erythromycin (see sample 67)C = 2′-deoxy-3′-dedimethylamino-2′,3′-epoxyazithomycin D = Ketolide fromdescladinosyl-azithromycin (oxidized at 3-OH), a hemiacetal with 6-OH isformed

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

CITATIONS

-   -   Alberola A., Antolin L. F., Gonzalez A. M., Laguna M. A., and        Pulido F. J.; J. Heterocyclic Chem; 23; 1035; (1986).    -   Alberola A., Antolin L. F., Gonzalez A. M., Pulido F. J.;        Base-induced Ring Cleavage of 4-Functionalized 3-Unsubstituted        Isoxazoles. Synthesis of 2-Aminopyrimidines and        Pyrimidine-2(3H)-thiones; Heterocycles; (1987).    -   Axton et al., 1992, J. Chem. Soc. Perkin Trans. I 2203 ff.    -   Bartlett et al., 1991, Agents and Actions, 32 10-21.    -   Benslay D N and Bendele A M, 1991, Agents Actions 34: 254.    -   Billingham et al., 1954. Proc. R. Soc. 143: 43-55.    -   Douthwaite S and Champney W S, 2001, J Antimicrob Chemother.        2001 September; 48 Suppl T1:1-8.    -   Elliot et al., 1998, J. Med. Chem. 41, 1651-1659.    -   Hutchins R O, Hoke D, Keogh J, Koharstki D, 1969, Sodium        Borohydride in Dimethyl Sulfoxide or Sulfolane. Convenient        Systems for Selective Redutions of Primary, Secondary, and        Certain Tertiary Halides and Tosylates. Tetrahedron Letters,        3495-3498.    -   Ianaro et al., 2000, Anti-inflammatory activity of Macrolide        Antibiotics. J. Pharmacol. Ex. Therapeutics. 292:156-161.    -   Labro M T and Abdelghaffar H, 2001, Immunomodulation by        macrolide antibiotics. J. Chemother. February; 13(1):3-8.        Review.    -   Labro M T, 1998, Anti-inflammatory activity of macrolides: a new        therapeutic potential? J. Antimicrobial Chemother. 41, Suppl.,        37-46.    -   Quallich L G, Greenson J, Haftel H M, Fontana R J, 2001, Is it        Crohn's disease? A severe systemic granulomatous reaction to        sulfasalazine in patient with rheumatoid arthritis, BMC        Gastroenterol; 1(1): 8.    -   Schroit A J, Madsen J, Nayar R, 1986, Liposome-cell        interactions: in vitro discrimination of uptake mechanism and in        vivo targeting strategies to mononuclear phagocytes., Chem Phys        Lipids. June-July; 40(2-4):373-93.

PATENTS AND PATENT PUBLICATIONS

PCT03/070174 February 2002 Burnet et al PCT03/070173 February 2002Burnet et al U.S. Pat. No. May 1982 Kobrehel et al. 536/7.4 4,328,334U.S. Pat. No. November 1969 Djokic et al. 536/9 3,478,014 U.S. Pat. No.March 1972 Massey 536/9 3,652,537 U.S. Pat. No. January 1991 Franco536/7.1 4,988,677 U.S. Pat. No. August 1996 Agouridas 514/646 5,543,400US2001/0053782A1 December 2000 Blumenkopf et al. 514/258 PCT03/070254A1February 2002 Burnet et al. WO2004029067 February 2003 Berdik et al.WO09/963937 July 1999 Griffin EP0283055 September 1988 Carevic andDjokic 540/467; 314/183 EP0627406A1 October 1992 Fujita et al. C07C215/10

What is claimed is:
 1. A compound represented by the formula:

wherein A and A′ are each hydrogen or taken together form a double bond,and A″ is H or OH or O-Cladinosyl; or A=Hydrogen and A′ and A″ takentogether represent ═O; R¹, R², R³, and R⁵ are independently selectedfrom the group consisting of H, alkyl, acyl, allyl, vinyl, SiR′₃ inwhich R′ is, independently for each occurrence, alkyl or aryl); or A andA″=Hydrogen and A′ and R¹ together represent a single bond; R², R³ maybe C═O (cyclic carbonate); R⁶═H, OH, CN, N₃, NR⁸ ₂ (in which each R⁸ isindependently H, alkyl or cycloalkyl), alkyl, cycloalkyl, —N(CH₃)R^(8′)(in which R^(8′) is H, alkyl, aryl, heteroaryl), or SR⁹ (in which R⁹ isH, alkyl or cycloalkyl); Q=—N(CH₃)—CH₂—; or a pharmaceuticallyacceptable salt thereof.
 2. A pharmaceutical composition comprising acompound of claim 1, or a pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable excipient.
 3. A method oftreating an inflammatory or bacterial, disorder, the method comprisingadministering to a subject in need thereof an effective amount of acompound of claim 1, such that the inflammatory or bacterial disorder istreated.